In order to devise more effective pharmacotherapies for patients with refractory mood disorders, we have begun studies of the clinical and pharmacokinetic effects of treatments with combinations of psychotropic agents. The aminoketone atypical antidepressant bupropion (BUP) is of particular interest, as it appears effective in refractory depression and may yield manic switches and rapid cycling less frequently than older antidepressant agents. However, seizures can occur during high dose BUP therapy. Combination of BUP with the mood stabilizing anticonvulsants carbamazepine (CBZ) or valproate (VPA) are strategies which could lessen the risks of both mania and seizures. Such therapies could be complicated by pharmacokinetic drug interactions, as CBZ induces hepatic metabolism of various medications, whereas valproate can inhibit hepatic metabolism. Preliminary data suggest that CBZ causes dramatic decreases in BUP levels an increases in levels of the metabolite hydroxybupropion (H-BUP), while VPA does not affect BUP levels and yields smaller increases in H-BUP. We plan to examine the relationships between such pharmacokinetic observations and clinical efficacy.